Dihydrorotenone (DHR) is a natural pesticide widely used in farming industry, such as organic produces. Dihydrorotenone is a potent mitochondrial inhibitor and probably induces Parkinsonian syndrome, however, it is not known whether Dihydrorotenone is toxic to other systems.
METHODS AND RESULTS:
In the present study, we evaluated the cytotoxicity of Dihydrorotenone on human plasma cells. As predicted, Dihydrorotenone impaired mitochondrial function by decreasing mitochondrial membrane potential in plasma cells. Because mito-dysfunction leads to unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, we examined the signature proteins in ER stress, including GRP78, ATF4, and CHOP. After Dihydrorotenone treatment, these proteins were significantly upregulated. It is reported that activation of the mitogen-activated protein kinases p38 and JNK are involved in endoplasmic reticulum stress. However, in the subsequent study, Dihydrorotenone was found to activate p38 but not the JNK signaling. When pre-treated with p38 inhibitor SB203580, activation of p38 and cell apoptosis induced by Dihydrorotenone was partially blocked.
CONCLUSIONS:
Thus, we found that Dihydrorotenoneinduced human plasma cell death by activating the p38 but not the JNK signaling pathway. Because plasma cells are very important in the immune system, this study provided a new insight in the safety evaluation of Dihydrorotenone application. |
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